The mesotelencephalic dopamine (DA) system is composed of relatively distinct DA systems originating in the midbrain and projecting to forebrain sites. The system exhibits considerable heterogeneity in anatomical, biochemical, and functional characteristics. However, recent data indicate that integrated action within the different DA subsystems occurs. Derangements of the integrated function of mesotelencephalic components (e.g., cortical, limbic, and striatal) may underlie schizophrenia. such changes may also help explain patient response to neurolpetics and the development of tardive dyskinesia. The functional interactions of the cortical and subcortical DA systems will be studied. The anatomical interconnections of the DA systems at the terminal field and cell body levels will be determined. The effects of prefrontal cortical (PFC) dopamine depletion on subcortical DA function will be examined. Specifically, effects of PFC DA lesions on biochemical indices of striatal and nucleus accumbens (NAS) DA function will be assessed; ex vivo (e.g., metabolite, synthesis), in vitro (TH activity), and in vivo (DA release measured by in vivo dialysis) approaches will be used. The effects of PFC DA depletion on both basal and activated DA function will be determined. Possible selective effects of PFC DA depletion on striatal DA compartments (islandic and diffuse DA systems) will be examined using biochemical and anatomical methods. The effects of PFC DA lesions on TH gene expression in identified mesolimbic and nigrostriatal neurons will be assessed with in situ hybridization histochemistry. The modulatory effects of PFC DA depletion on behavior subserved by subcortical DA systems will be examined. Similar strategies will be used to study the functional interactions of the DA systems at the cell body level (i.e., through interconnections of the A8, A9, and A10 cell groups), in particular focusing on the regulation of mesocortical DA function by non-mesocortical dopaminergic neurons. Such studies of the functional interaction of mesotelencephalic DA neurons may help in understanding the development of schizophrenia.